On the surface, testosterone therapy is a controversial treatment because previous studies investigating the effects of testosterone therapy have been conflicting, with some studies showing supposed harm and others showing significant benefit.

Here we present the results of a new study published in The Lancet Diabetes & Endocrinology on May 7 2016, which addressed some shortcomings in previous studies by analyzing effects based on duration of testosterone treatment.1

Key Points

After a follow-up for over 5 years, men treated with testosterone had 12% lower mortality than non-testosterone treated men.

Compared to non-testosterone treated men, men with the shortest duration of testosterone treatment had 11% increased risk of mortality and 26% increased risk cardiovascular events. In contrast, those with the longest duration of testosterone treatment had 33% decreased risk of mortality and 16% decreased risk of cardiovascular events.

Risk of prostate cancer diagnosis was decreased by 40% in men with the longest duration of testosterone treatment, compared to non-testosterone treated men. No effect on prostate cancer risk was seen among men with shortest duration of testosterone treatment.

It is speculated that the increased risk of cardiovascular events and mortality for men with the shortest duration of testosterone treatment could be driven by the consequences of underlying testosterone deficiency and inadequate treatment, rather than the testosterone treatment.

What is known

The health consequences of testosterone deficiency, and the benefits of its treatment - such as improvement in sexual function, mood, body composition and metabolic risk factors - are well established in medical research.2 Despite this, testosterone therapy is controversial. Concerns regarding cardiovascular risk were based on two deeply flawed retrospective studies, which we discussed in a previous editorial “Testosterone Therapy and Cardiovascular Risk - Advances and Controversies”.

Despite the multiple flaws of these two studies, they led the US Food and Drug Administration (FDA) to issue a warning that testosterone therapy might increase risk of heart attack and stroke.3

This supposed harm is strongly refuted by many studies showing cardiovascular benefits of higher endogenous testosterone as well as testosterone therapy, including placebo-controlled studies in men with known heart disease (angina, heart failure).4,5 In addition, 3 large meta-analyses have refuted a supposed causal role between testosterone therapy and adverse cardiovascular disease events.6-8 To the contrary, in randomized controlled trials – the gold standard study type in clinical research - performed in subjects with metabolic derangements (which constitute about half of the general population9-12) a protective effect of testosterone therapy on cardiovascular disease risk was observed.7 More recently, as summarized in table 1, numerous additional observational studies have confirmed that low testosterone levels are associated with heart disease and that testosterone therapy confers beneficial effects, or is at worst neutral in terms of cardiovascular disease outcomes and mortality.

Table 1: Studies published after Vigen and Finkle that refute supposed harms.

What this study adds

The Lancet study sought to assess the effect of testosterone therapy on overall mortality and cardiovascular events in men with long-term follow-up using a time-varying testosterone exposure, in order to find out if duration of testosterone treatment impacts outcomes. Prostate cancer was also examined because testosterone therapy has historically been considered a risk factor for developing prostate cancer, even though recent studies have disproved this (see comment below).

10,749 men aged 66 years or older who were treated with testosterone therapy were matched for age, comorbidity, diabetes, region of residence, with 28,029 controls (i.e. men who did not receive testosterone therapy). The study assessed the effect of testosterone therapy in two ways; testosterone treatment as a dichotomous variable (any or never), and total testosterone treatment duration (cumulative testosterone exposure) divided into groups of 1-3 months, 6-12 months and 25-51 months. Testosterone treatment duration was measured by the total number of days of testosterone therapy dispensed according to prescription records.

When the effect of testosterone therapy was examined as a dichotomous variable, 5-year mortality was significantly lower in men treated with testosterone therapy (15.4%) than in controls (17.7%).

To examine the effect of testosterone treatment duration, men were divided into three groups; lowest, middle and highest testosterone treatment duration. Men with the lowest group had higher mortality than controls, but those in the middle and highest groups had lower mortality than controls. The risk of mortality was progressively lower with increasing duration of testosterone therapy, with a significantly decreased risk for men who had been treated with testosterone for the longest duration.

5-year incidence of cardiovascular events did not differ significantly between testosterone treated men and controls, but the 5-year incidence of prostate cancer diagnoses was 14% lower in the testosterone treated men.

When analyzing the results based on testosterone treatment duration, men who had been on testosterone for the shortest duration had a 26% higher incidence of cardiovascular events than did controls, but men who had been on testosterone for the longest duration had 16% lower incidence than controls. Similarly, men who had been on testosterone for the shortest duration had the equivalent rates of prostate cancer diagnosis to controls, whereas those who had been on testosterone for the longest duration had 40% less prostate cancer diagnoses than controls.

Comments

This study is the first study to assess the effect of different durations of testosterone therapy on mortality and cardiovascular events. The results of this analysis explain previous conflicting findings of the effect of testosterone therapy on cardiovascular events.

With a large number of subjects and long duration of follow-up, long-term testosterone therapy was found to reduce both mortality, cardiovascular events and prostate cancer, while short-term testosterone therapy may increase mortality and cardiovascular events. Thus, if there is short-term risk, it dissipates over time with ongoing treatment.

In a previous study that showed increased risk of myocardial infarction after initiation of testosterone therapy, treatment duration and follow-up were limited to only 90 days. As indicated in table 1, the study by Etminan et al. also found a small increased risk of heart attack in first-time users.23 However, as the absolute risk was low, the clinical significance of this minor risk increase is questionable.

It has been documented that full expression of the effects of testosterone therapy take many years.29 Considering the well-documented adverse health effects of testosterone deficiency2,30-32, the authors of this study appropriately suggest that the reason for the increased rates of cardiovascular events and mortality in the short-term treatment group could be driven by the consequences of underlying testosterone deficiency and inadequate treatment, rather than the testosterone treatment.

This study also confirms the safety of testosterone therapy in terms of prostate cancer.